Cystinuria is an inherited autosomal recessive disease characterized by high

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', ''number concentration'', ...

s of the amino acid

cystine Cystine is the oxidized derivative of the amino acid cysteine and has the formula (SCH2CH(NH2)CO2H)2. It is a white solid that is poorly soluble in water. As a residue in proteins, cystine serves two functions: a site of redox reactions and a mec ...

in the

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellul ...

, leading to the formation of

stones in the

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

s, ureters, and

bladder The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine en ...

. It is a type of aminoaciduria. "Cystine", not "cysteine," is implicated in this disease; the former is a

dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius Dimer ( ...

of the latter.

Presentation

Cystinuria is a cause of recurrent kidney stones. It is a disease involving the defective transepithelial transport of cystine and dibasic amino acids in the kidney and intestine, and is one of many causes of kidney stones. If not treated properly, the disease could cause serious damage to the kidneys and surrounding organs, and in some rare cases death. The stones may be identified by a positive nitroprusside cyanide test. The crystals are usually hexagonal, translucent, white. Upon removal, the stones may be pink or yellow in color, but later they turn to greenish due to exposure to air. Cystinuria is usually asymptomatic when no stone is formed. However, once a stone is formed, signs and symptoms can occur: * Nausea * Flank pain * Hematuria *

Urinary tract infection A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidne ...

s * Rarely,

acute Acute may refer to: Science and technology * Acute angle ** Acute triangle ** Acute, a leaf shape in the glossary of leaf morphology * Acute (medicine), a disease that it is of short duration and of recent onset. ** Acute toxicity, the adverse ef ...

chronic kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...

People with cystinuria pass stones monthly, weekly, or daily, and need ongoing care. Cystinurics have an increased risk for chronic kidney disease and since kidney damage or poor function is often present in cystinurics, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or over the counter (OTC) medications should be used with caution. Cystine stones are often difficult to detect using plain x-rays. Computed tomography or

ultrasound Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. This limit varies ...

may be used instead for imaging. Urine odor in cystinuria has a smell of rotten eggs due to the increase in cystine.

Genetics

Cystinuria is an autosomal recessive disease, which means that the defective gene responsible for the disease is located on an

autosome An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosomes ...

, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disease. The parents of an individual with an autosomal recessive disease both

carry Carry or carrying may refer to: People *Carry (name) Finance * Carried interest (or carry), the share of profits in an investment fund paid to the fund manager * Carry (investment), a financial term: the carry of an asset is the gain or cost of h ...

one copy of the defective gene, but usually do not experience any signs or symptoms of the disease. Although signs and symptoms are rare, there are some directly and indirectly associated with cystinuria. These sign and symptoms consist of 1) hematuria- blood in the urine, 2) flank pain – pain in the side due to kidney pain, 3) renal colic – intense, cramping pain due to stones in the urinary tract, 4) obstructive uropathy- urinary tract disease due to obstruction, and 5) urinary tract infections.

Cause

Cystinuria is caused by mutations in the '' SLC3A1'' and '' SLC7A9'' genes. These defects prevent proper reabsorption of basic, or positively charged, amino acids:

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated − ...

ornithine Ornithine is a non-proteinogenic amino acid that plays a role in the urea cycle. Ornithine is abnormally accumulated in the body in ornithine transcarbamylase deficiency. The radical is ornithyl. Role in urea cycle L-Ornithine is one of the produ ...

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

. Under normal circumstances, this protein allows certain amino acids, including cystine, to be reabsorbed into the blood from the filtered fluid that will become urine. Mutations in either of these genes disrupt the ability of this transporter protein to reabsorb these amino acids, allowing them to become concentrated in the urine. As the levels of cystine in the urine increase, it forms

crystals, resulting in kidney stones. Cystine crystals form hexagonal-shaped crystals that can be viewed upon microscopic analysis of the urine. The other amino acids that are not reabsorbed do not create crystals in urine. The overall

prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...

of cystinuria is approximately 1 in 7,000 neonates (from 1 in 2,500 neonates in

Libyan Demographics of Libya is the demography of Libya, specifically covering population density, ethnicity, education level, health of the populace, economic status, and religious affiliations, as well as other aspects of the Libyan population. The ...

Jew Jews ( he, יְהוּדִים, , ) or Jewish people are an ethnoreligious group and nation originating from the Israelites Israelite origins and kingdom: "The first act in the long drama of Jewish history is the age of the Israelites""T ...

s to 1 in 100,000 among

Swedes Swedes ( sv, svenskar) are a North Germanic ethnic group native to the Nordic region, primarily their nation state of Sweden, who share a common ancestry, culture, history and language. They mostly inhabit Sweden and the other Nordic countr ...

Pathophysiology

Cystinuria is characterized by the inadequate reabsorption of cystine in the proximal convoluted tubules after the filtering of the amino acids by the kidney's glomeruli, thus resulting in an excessive concentration of this

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

in the urine. Cystine may precipitate out of the

, if the urine is neutral or acidic, and form

crystal A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macro ...

s or stones in the kidneys, ureters, or bladder. It is one of several

inborn errors of metabolism Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances ( substra ...

included in the Garrod's tetrad. The disease is attributed to deficiency in transport and metabolism of amino acids.

Diagnosis

# Blood: Routine hemogram along with blood sugar, urea, and creatinine. # Urine: For cystine crystals, and casts. The most specific test is the cyanide–nitroprusside test # Ultrasound/CT scan to reveal if a stone is present. # Genetic analysis to determine which mutation associated with the disease may be present. Currently genotyping is not available in the United States but might be available in Spain, Italy, UK, Germany and Russia (by private companies in Germany and Russia). Regular X-rays often fail to show the cystine stones, however they can be visualized in the diagnostic procedure that is called intravenous pyelogram (IVP). Stones may show up on XR with a fuzzy gray appearance. They are radioopaque due to sulfur content, though more difficult to visualize than calcium oxalate stones.

Treatment

Initial treatment is with adequate hydration, alkalization of the urine with citrate supplementation or acetazolamide, and dietary modification to reduce salt and protein intake (especially

methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ...

). If this fails then patients are usually started on

chelation therapy Chelation therapy is a medical procedure that involves the administration of chelating agents to remove heavy metals from the body. Chelation therapy has a long history of use in clinical toxicology and remains in use for some very specific me ...

with an agent such as

penicillamine Penicillamine, sold under the brand name of Cuprimine among others, is a medication primarily used for the treatment of Wilson's disease. It is also used for people with kidney stones who have high urine cystine levels, rheumatoid arthritis, ...

. Tiopronin is another agent. Once renal stones have formed, however, the first-line treatment is endoscopic laser lithotripsy. ESWL (

Extracorporeal shock wave lithotripsy Extracorporeal shockwave therapy (ESWT) is a non-invasive, out-patient alternative to surgery for those with many joint and tendon disorders. ESWT sends acoustic shock waves into bone or soft tissue, in effect reinjuring the area on a cellular l ...

) is often not effective because of the hardness of the stones that do not fragment easily. Conventional open-abdominal surgery is rarely used but has proven to be effective treatment modalities for patients with more advanced disease. Adequate hydration is the foremost aim of treatment to prevent cystine stones. The goal is to increase the urine volume because the concentration of cystine in the urine is reduced which prevents cystine from precipitating from the urine and forming stones. People with cystine stones should consume 5 to 7 liters a day. The rationale behind alkalizing the urine is that cystine tends to stay in solution and causes no harm. In order to alkalize the urine, sodium bicarbonate has been used. One must be careful in alkalizing their urine because it could lead to other forms of stones in process of preventing cystine stones. Penicillamine is a drug that acts to form a complex with cystine that is 50 times more soluble than cystine itself. Percutaneous nephrolithotripsy (PNL) is performed via a port created by puncturing the kidney through the skin and enlarging the access port to 1 cm in diameter. Most of the time, cystine stones are too dense to be broken up by shock (ESWL) so PNL is needed. Videos of surgery are available on various websites that show stone removal by percutaneous nephrolithotomy. In February 2017, an article was published in ''Nature Medicine'' entitled "Alpha lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria", suggesting that a high dose of the readily available antioxidant, alpha-lipoic acid at 2,700 mg/67 kg body weight daily reduced the incidence of stones. The effects were dose dependent. The results are unprecedented for cystinuria. A clinical trial is underway based on this mouse model.

Occurrence in animals

This disease is known to occur in at least four

mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur ...

ian species:

human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, cultu ...

s, domestic canines, domestic ferrets and a wild canid, the

maned wolf The maned wolf (''Chrysocyon brachyurus'') is a large canine of South America. It is found in Argentina, Brazil, Bolivia, Peru, and Paraguay, and is almost extinct in Uruguay. Its markings resemble those of foxes, but it is neither a fox nor a w ...

South America South America is a continent entirely in the Western Hemisphere and mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere at the northern tip of the continent. It can also be described as the sou ...

. Cystine uroliths have been demonstrated, usually in male dogs, from approximately 70 breeds including the Australian cattle dog, Australian shepherd, Basenji, Basset, Bullmastiff, Chihuahua, Scottish deerhound, Scottish terrier, Staffordshire terrier, Welsh corgi, and both male and female Newfoundland dogs.

References

External links

{{Membrane transport protein disorders Amino acid metabolism disorders Autosomal recessive disorders Membrane transport protein disorders